Clinical Topics & News
Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia
Understanding signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease...
Low-dose cytarabine in combination with valproic acid and all-transretinoic acid (ATRA) is used in stabilizing treatment for patients with acute myeloid leukemia (AML) who aren’t candidates for intensive therapy. In vivo studies have shown that the triple-drug treatment has immunomodulatory effects. But researchers from University of Bergen, Norway, say little was known about both the acute and long-term effects of such treatment on the T-cell system.
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To find out, they conducted an in vitro study to examine the effects of cytarabine, valproic acid, and ATRA on activated T cells, testing cytarabine at concentrations reached during in vivo treatment with high doses, conventional doses, and low doses.
The researchers found that cytarabine—especially when combined with valproic acid and ATRA—can reduce T-cell viability and proliferation, alter the activation-induced expression of membrane molecules, and reduce the release of several cytokines. Cytarabine’s effects on T-cell activation were concentration dependent: Reduced viability was seen only at the higher concentrations. However, the researchers note that cytarabine had immunoregulatory effects even at lower levels. When cytarabine was combined with valproic acid and ATRA, the researchers observed no or minor effects on T-cell viability.
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Only cytarabine 44 μM had both antiproliferative and proapoptotic effects. The drug reduced AML cell viability only at 0.5 and 0.05 μM, not at the lowest concentration; but it inhibited AML cell proliferation even at 0.01 μM. By contrast, T-cell proliferation was inhibited only at concentrations ≥ 0.35 μM.
Based on the proliferation studies, the researchers conclude that primary AML cells are more susceptible to cytarabine than are normal T cells, which suggests, they add, a therapeutic window for cytarabine treatment that “makes it possible to achieve antileukemic effects in vivo before severe T-cell toxicity occurs.”
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The triple-drug combination’s direct effects on the T cells may be offset by other effects on immunocompetent cells; the researchers say the possible risk of immunosuppression should be further investigated.
Source
Ersvaer E, Brenner AK, Vetås K, Reikvam H, Bruserud Ø. BMC Pharmacol Toxicol. 2015;16:12.
doi: 10.1186/s40360-015-0012-2.
